Box 2 MAJOR RESEARCH ISSUES FOR INDIVIDUALS WITH PITT-HOPKINS SYNDROME

MAJOR RESEARCH ISSUES FOR INDIVIDUALS WITH PITT-HOPKINS SYNDROME

• What is the natural history of Pitt-Hopkins syndrome in adults and older individuals?
• Breathing anomalies: what are the long-term consequences of breathing anomalies, both physically and cognitively?
• What is the prevalence of obstructive sleep apnoea?
• Can breathing anomalies be decreased if needed?
• Seizures: are seizures primary or consequences of breathing anomalies?
• Other symptoms caused by autonomic nervous system dysregulation: what is the exact pathogenesis? If needed, can consequences (especially drooling and constipation) be influenced?
• Immune system: what are the consequences of PTHS variants causing Pitt-Hopkins syndrome for immunological
  functioning, including reactions to vaccination?
• Motor functioning: what is the pathogenesis of the foot position anomalies? Can physical therapy, drugs or surgical procedures effectively influence these anomalies?
• Communication: what are the communication abilities?
• Are there biomarkers that predict these abilities? Which approach best increases communicative abilities?
• Behaviour: what are the specific characteristics of autism or autism spectrum disorder in individuals with Pitt-Hopkins syndrome? In which way do factors such as autonomic dysregulations, food or other environmental factors influence behaviour?
• Is it possible to address behavioural difficulties effectively through psychotherapy, contextual adjustments and/or drugs if needed?

• Genotype – phenotype correlations
• Molecular characteristics: can a functional study be developed that indicates with sufficient certainty causality of a Pitt-Hopkins phenotype? Can the mRNA derived from the wild type allele be stabilized in vitro? Does this lead to increase protein formation and if so, does this influence the consequences of haplotype insufficiency for TCF4 in animal models?